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X-Inactivation by Chromosomal Pairing Events Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE X-inactivation by chromosomal pairing events York Marahrens1,2 1Department of Human Genetics, University of California at Los Angeles (UCLA), Los Angeles, California 90095 USA X-inactivation is the coordinated silencing of nearly all Dosage compensation is the coordinate regulation of genes on one of the two X chromosomes in female mam- X-linked genes by chromatin remodeling to provide the mals. X-inactivation requires the cis-acting Xist gene. two sexes, which have a twofold difference in X chromo- The highly unusual properties of Xist and the extremely some number, with equal levels of X chromosomal gene long distances over which Xist acts have made it difficult expression. In Drosophila, this is accomplished by large to reconcile X-inactivation with other examples of gene numbers of cis-acting elements, each of which controls a regulation. This paper presents new findings that suggest single gene or a small group of adjacent genes (Baker et that X-inactivation involves transvection and harnesses al. 1994). These elements up-regulate gene expression heterochromatin association. twofold on the single male X chromosome by ‘loosening’ the chromatin of each gene to make it more euchro- matic. In Caenorhabditis elegans, proteins associate Role of chromatin in dosage compensation with numerous sites along both of the X chromosomes of Chromatin is the complex of DNA, histones, and other the XX individuals, down-regulating gene expression factors that compose chromosomes. Originally, eukary- twofold by making each X chromosome slightly more otic chromosomes were believed to consist of euchroma- heterochromatic (Nicoll et al. 1997; Dawes et al. 1999). tin, regions that permit gene expression, and heterochro- The chromatin adjustments that produce twofold matin, chromosomal regions that are condensed and re- changes in gene expression in Drosophila and C. elegans pressive to gene function (Heitz 1928; Karpen 1994). In underscore that a spectrum of chromatin structures are general, the DNA of heterochromatin is more heavily possible, spanning from very heterochromatic to very eu- methylated (in organisms that have DNA methylation) chromatic. (Selker 1990; Klein and Costa 1997; Garrick et al. 1998), Dosage compensation in mammals (X-inactivation) is and replicates later in S phase (Taylor 1960) than the fundamentally different from dosage compensation in DNA of euchromatin. The histones of heterochromatin Drosophila and C. elegans. The mammalian cell is are also less acetylated (Turner 1998). Several lines of thought to first ‘count’ the X chromosomes and, if two X evidence indicate that the terms euchromatin and het- chromosomes are present, activate the X-inactivation erochromatin should both be considered umbrella terms pathway. Rather than regulating all of the X-linked genes for multiple chromatin structures. in a cell equally, the cell ‘chooses’ one X chromosome to There are two types of heterochromatin, constitutive be inactivated through the spread of heterochromatin ∼ heterochromatin and facultative heterochromatin. Con- across 160 Mb. The Xist locus is involved in all three stitutive heterochromatin forms over repetitive se- processes, namely counting, choosing, and long distance quence and serves to maintain genome stability. Consti- heterochromatin formation. Xist, therefore, is required tutive heterochromatin suppresses recombination be- for chromatin remodeling over a far greater distance than tween repetitive sequences and subdues the mutagenic any other known cis-acting locus. potential of transposons by keeping them constitutively The Xist gene was first identified when a large (15 kb) inactive (Yoder et al. 1997; Jensen et al. 1999). This is untranslated RNA was cloned that is expressed exclu- important, as ∼35% of the human genome consists of sively from the inactive X chromosome (Borsani et al. repetitive transposon DNA sequence (Yoder et al. 1997). 1991; Brown et al. 1991). Interestingly, the Xist RNA In contrast, facultative heterochromatin is formed and associates exclusively with the inactive X chromosome dismantled in a controlled manner by specific chromatin (Brown et al. 1992; Clemson et al. 1996; Panning and control sequences to regulate gene expression. The abil- Jaenisch 1996). Targeted mutagenesis revealed that Xist- ity of specific chromatin structures to spread to nearby deficient X chromosomes are incapable of being inacti- genes allows gene expression to be regulated. vated in cultured cells (Penny et al. 1996) or during em- bryogenesis (Marahrens et al. 1997). A surprising discov- ery was the finding that a 450-kb transgene, that 2Corresponding author. includes the Xist locus, could inactivate an autosome E-MAIL [email protected]; FAX (310) 794-5446. (Lee et al. 1996; Lee and Jaenisch 1997). The sequence 2624 GENES & DEVELOPMENT 13:2624–2632 © 1999 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/99 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press X-inactivation by chromosomal pairing required for Xist transgene-mediated inactivation was random (Penny et al. 1996) and imprinted (Marahrens et subsequently narrowed down to a 35 kb region that con- al. 1997) X-inactivation, demonstrating that the two tains the Xist transcribed region and 9 kb of upstream types of X-inactivation are mechanistically related. sequence (Herzing et al. 1997). Three different parameters indicate that, for both X- The highly distinctive properties of Xist and the ex- inactivation and autosomal imprinting, the allelic re- tremely long distance effects of the X-inactivation pro- gions in question differ in their chromatin structures. cess have made it difficult to reconcile X-inactivation First, extensive differences in methylation have been re- with other examples of gene regulation by chromatin. ported between the active and inactive X chromosomes However, it is highly unlikely that a new and fundamen- (Mohandas et al. 1981; Migeon 1990) and between the tally different biological process has evolved to take care two copies of autosomal imprinted regions (Bartolomei of the X chromosome gene dosage problem in mammals. and Tilghman 1997). Demethylation results in loss of The available evidence overwhelmingly indicates that allelic differences in gene expression for both imprinted basic biological processes are conserved among diverse genes (Li et al. 1993) and for the X chromosome (Beard et organisms. al. 1995; Panning and Jaenisch 1996). Second, the his- In this paper I consider the possibility that the pro- tones of heterochromatin are less acetylated than in eu- cesses responsible for X-inactivation are not unique to chromatin (Grunstein 1997; Turner 1998). The inactive X-inactivation. I first highlight significant functional X chromosome is less acetylated than the active X chro- similarities between genomic imprinting and X-inacti- mosome (Jeppesen and Turner 1993). The treatment of vation which culminate in recent findings by Rolf Ohls- cells undergoing X-inactivation with trichostatin, a his- son and colleagues. In considering these similarities, I tone deacetylase inhibitor presented normal inactivation propose that X-chromosome counting, choosing, and the (O’Neill et al. 1999). Trichostatin treatment of mouse initiation of heterochromatin formation are the genetic conceptuses attempting to establish the monoallelic ex- consequence of physical pairing interactions between pression pattern of the imprinted H19 gene similarly dis- the homologous X chromosomes (transvection). I next rupts the silencing of one allele of the H19 gene (Svens- discuss recent evidence presented by Lyon (1998) that son et al. 1998). Finally, heterochromatin is later repli- indicates the spread of heterochromatin over long dis- cating than euchromatin and chromatin has been shown tances is brought about by interactions involving repeti- to be an important determinant of replication origin tim- tive elements distributed throughout the X chromo- ing (Fangman and Brewer 1992). Both imprinted genes some. In light of recent findings by Gartler and col- (Kitsberg et al. 1993) and X-chromosomal genes in fe- leagues (1999), Kominami and colleagues, and Henikoff males (Ohno and Hauschka 1960; Taylor 1960) are early and coworkers, I suggest that heterochromatin associa- replicating on one homologous chromosome and late tion is harnessed to control gene expression levels by replicating on the other. heterochromatin spreading. Finally, I show how this new For some examples of autosomal imprinting and X- view of X-inactivation can be adapted in a straightfor- inactivation, chromatin differences between the ho- ward manner to explain reports of skewed X-inactiva- mologous chromosomes span large regions. Many, but tion. The mechanisms discussed are useful in under- not all imprinted genes are grouped into megabase-sized standing a rapidly increasing number of characterized clusters. Some mutations within these gene clusters ex- genetic diseases. hibit long distance effects on gene expression. One of the best studied imprinted clusters is on human chromo- some 15 and is implicated in both Prader-Willi syndrome (PWS) and Angelman syndrome (AS) (Mutirangura et al. Similarities between autosomal imprinting 1993; Driscoll 1994; DeLorey et al. 1998). Some PWS and and X-inactivation AS patients carry mutations in this imprinted gene clus- Important
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